Tobacco smoking is a major cause of morbidity and mortality in the United States and other industrialized countries. Understanding why some smokers develop lung cancer, and others do not, will lead to improved population and individual risk assessment methods, and focus prevention strategies. Host susceptibilities may play a role in nicotine dependence through interindividual variation in nicotine metabolism or neurobehavioral factors that relate to the reinforcing value of nicotine. The former might dictate the initial pharmacological reactions to nicotine and how much smoking is needed to maintain nicotine levels, while the latter may affect why people need to maintain nicotine levels. We have performed a study of 233 smokers and 233 nonsmokers, free of cancer and recruited through local media in Washington, DC and Philadelphia, in order to explore gene- neurobehavioral risk factors for smoking. We have found that a gene- gene interaction for polymorphisms in the dopamine transporter and dopamine D2 receptor was indeed predictive of smoking. Those persons who did smoke and have the combined decreased risk genes had longer times for quitting, when they were able to quit. These data, based upon the knowledge that nicotine stimulates the secretion of dopamine, which in turn stimulates reward mechanisms, is consistent with the hypothesis that the need for synaptic dopamine and stimulation of the dopamine D2 receptors predicts addiction if someone smokes cigarettes. We also evaluated smoking risk and smoking cessation and depression with a dopamine D4 receptor 48 base pair VNTR polymorphism, and found a significant interaction (D4 X depression) for stimulation smoking and negative affect reduction smoking. Specifically, these smoking practices were significantly heightened in depressed smokers with DRD4 S/S genotypes, but not the others. Other genetic polymorphisms also were examined, but no associations were found. These include polymorhpisms in the tyrosine hydroxylase, and serotonin transporter. - Lung cancer, Tobacco Smoking, - Human Tissues, Fluids, Cells, etc.